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Hematologic and systemic metabolic alterations due to Mediterranean class II G6PD deficiency in mice
Angelo D’Alessandro, … , Tiffany Thomas, James C. Zimring
Angelo D’Alessandro, … , Tiffany Thomas, James C. Zimring
Published June 17, 2021
Citation Information: JCI Insight. 2021;6(14):e147056. https://doi.org/10.1172/jci.insight.147056.
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Research Article Hematology

Hematologic and systemic metabolic alterations due to Mediterranean class II G6PD deficiency in mice

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Abstract

Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (approximately 5%). Its prevalence is hypothesized to be due to conferring resistance to malaria. However, G6PD deficiency also results in hemolytic sequelae from oxidant stress. Moreover, G6PD deficiency is associated with kidney disease, diabetes, pulmonary hypertension, immunological defects, and neurodegenerative diseases. To date, the only available mouse models have decreased levels of WT stable G6PD caused by promoter mutations. However, human G6PD mutations are missense mutations that result in decreased enzymatic stability. As such, this results in very low activity in red blood cells (RBCs) that cannot synthesize new protein. To generate a more accurate model, the human sequence for a severe form of G6PD deficiency, Med(-), was knocked into the murine G6PD locus. As predicted, G6PD levels were extremely low in RBCs, and deficient mice had increased hemolytic sequelae to oxidant stress. Nonerythroid organs had metabolic changes consistent with mild G6PD deficiency, consistent with what has been observed in humans. Juxtaposition of G6PD-deficient and WT mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and advance our basic understanding of altered metabolism in this setting.

Authors

Angelo D’Alessandro, Heather L. Howie, Ariel M. Hay, Karolina H. Dziewulska, Benjamin C. Brown, Matthew J. Wither, Matthew Karafin, Elizabeth F. Stone, Steven L. Spitalnik, Eldad A. Hod, Richard O. Francis, Xiaoyun Fu, Tiffany Thomas, James C. Zimring

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Figure 2

Metabolic effect of diamide challenge in RBCs from WT and G6PDMed- mice.

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Metabolic effect of diamide challenge in RBCs from WT and G6PDMed- mice....
RBCs from WT and G6PDMed- mice were incubated with 1 mM diamide (A). RBCs were tested at 0 minutes (no diamide), 30 minutes, 1 hour, 2 hours, 6 hours, and 12 hours from incubation with diamide prior to metabolomics analysis. Multivariate analyses including PLS-DA (B) and hierarchical clustering analysis (C) clearly indicate a time-dependent effect of the treatment on RBCs (PC1 explaining 45.5% of the total variance) and highlight the impact of G6PD activity (PC3 explaining 10.7% of the total variance). Significant metabolites by repeated measures 1-way ANOVA are shown in the heatmap in C. (D) The experiment was repeated by incubating RBCs in the presence of [1,2,3-13C3]-glucose. By quantifying isotopologs M+2 and M+3 of lactate (and the relative ratio), fluxes through PPP versus glycolysis can be determined (E — median ± range) and confirm a significantly lower activation of this pathway in RBCs from G6PDMed- mice upon diamide challenge. n = 4 for both groups. **P < 0.01, ***P < 0.001. EMP, Embden-Meyerhof-Parnas.

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